LU82163A1 - NOVEL PENICILLANIC ACID DERIVATIVES USEFUL IN PARTICULAR AS ANTIBIOTICS AND PROCESSES FOR THEIR PREPARATION - Google Patents

Description

H 1 -SEYS ^ EIII-derivatives of genicillanic acid jjtiles jaota ^ ent_conme §5Ëi ^ i2ËiSH§8_ëÈ_ ^ êürs_EÎ2 £ i - § - S_EEéB5HÎÎ2ï ·

The present invention relates to compounds of the ß-lactarae type hitherto unknown, including their acid addition salts, in particular with non-toxic acids which are acceptable in pharmacy, their preparation methods, the pharmaceutical compositions containing 5 the new compounds, the dosage units of these compositions and their applications to the treatment of patients suffering from infectious diseases.

The invention relates to novel compounds useful in the treatment of bacterial infections. The new compounds are particularly active against bacteria producing ß-lacta-ma se.

The compounds of the invention, which are antibiotics of interest in human and veterinary medicine, are represented by the general formula

3 p.m. S

V ^ y: / \ / I \ '(I)) - * - 7'. *

0 ^ H 'C — 0 - CH. — A

He I

0 r2 20 in which R ^ represents a 5 * 10-membered aaacycloalkyl or azabicycloalkyl radical, linked by the nitrogen atom and optionally substituted by one or two identical or different lower alkyl groups, such as methyl, ethyl, propyl , ieopropyl, butyl, isobutyl, sec-butyl and tert-butyl; represents a hydrogen atom or a lower alkyl, aryl or arylalkyl radical, and the asterisk in the remaining ester indicates a chiral center in cases where R ^ is different from hydrogen; A represents a radical of a ß-lactamase inhibitor containing a ß-lactam nucleus as well as a carboxy group, A being linked by the carboxy group. More particularly, / 30 A is represented by one of the general formulas-II, III or IV A / î • »H 2 \ p

R R3 H '' Rc H -H H J

"V — r ^ N ·" 'V-KNr —i ^ r

i IH

1 "/ —H ··, 0 '+ - ιι — λ | 5 0 N C-0- H. C-0- H C-0- 5 h »» 0 0 0

I II III IV

in which R "represents a hydrogen or halogen atom; , I R ^ is a hydrogen atom or an amino or acylarnino group, but i. 10 * one to the monk of the residues R ^ and ^ is hydrogen; R ,. represents a.

1 ,. halogen atom; and Rg represents a hydroxy group or one of the radicals of the known derivatives of clavulanic acid endowed with activity I inhibiting the β-lactamase.

Generally, the term "lower alkyl" denotes a straight chain or branched hryl alkyl radical "denotes a radical [carbocyclic, mono- or bicyclic and hcylaraino" denotes a radical present in the side chain of well known penicillins .

Particularly interesting compounds are those in which R ^ represents a piperidino residue, hexahydro-1H-azé-20 pine-l-yle, hexahydro-l (2H) -azocine-l-yle, octahydro-1H-azonine-ly] ^ Î2-methylhexahydro-III-azepine-1-yl, 3-methylhexahydro-1H-azepine-ly] ^ 4-methylhexahydro-1H-azepine-1-yl, 2,6-dlmethylpiperidino, cis-3-aza-I bicyclo [ 3.3.0] octyl-3 or cis-8-azabicyclo [4.3.0] nonyl-8; and R ^ j represents hydrogen or a methyl, ethyl, phenyl or benzyl group.

The possible presence of one or more chiral centers in Rp as well as in the rest of the ester (indicated by an asterisk),) | M

I; may give rise to the existence of several diastereomeric forms, compounds of general formula I. The invention covers all. The 1 30 diastereomeric forms of the compounds of formula I, as well as their.

j mixtures.

ί As indicated above, the invention also relates to sels the salts of the esters of formula I with non-toxic acids accepted in pharmacy, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acid sulfuric, / j: nitric acid, p-toluenesulfonic acid, methane acid on ionic 1 / ^ '1' formic acid, acetic acid, propionic acid, citric acid, / n /

T

* 3 tartaric acid, maleic acid, pamoic acid and p- (dipropyl-sulfamyl) benzoic acid (probenecid), without these examples being limiting of the invention. The salts formed with acidic antibiotics are also part of the invention. In some cases it is preferred to use readily soluble salts, while for other applications it may be convenient to use a sparingly soluble salt, for example to obtain a prolonged effect. In particular, a prolonged effect can be obtained by using a salt with probenecid which blocks the tubular excretion of ß-lactams.

It is well known that certain 6-amidinopenylcilanic acids are useful antibiotics with an effect: particularly good against many Gram negative bacteria.

However, they are insufficiently absorbed when administered orally and are therefore mainly used by parenteral routes. For oral administration, easily hydrolyzable esters of these compounds are used, for example acyloxyalkyl esters, unlike free acids easily absorbed from the gastrointestinal tract. These esters can be alkanoyloxy-alkyl esters, but also include the 0,0-bis-acyl derivatives of aldehyde hydrates of 6-aminopenicillanic acids. The latter compounds are described in the patent application of the Federal Republic of Germany DOS No. 27 16 172.

In the clinical treatment of bacterial infections, however, a serious problem is that there is an increasing frequency of bacteria producing β-lactamase. These enzymes inactivate most ß-lactam antibiotics and it is well established that the ß-lactamases of gram positive and gram negative bacteria significantly contribute to the resistance of bacteria to ß-lactam antibiotics.

Many natural inhibitors of β-lactamase have been described, including clavulanic acid and olivanic acid. More recently, it has been found that a number of semi-synthetic β-lactaraes, e.g. penicillanic acid 1,1-dioxide, 6a-chloropenicillanic acid 1,1-dioxide, a series of acid derivatives clavu-35 lanic, 6β-halopenicillanic acids, such as ß-brenp-penicillanic acid, methicillinsulfone and quinacillinesulfone, have similar biological properties. With few exceptions, A / -----— - 4 against most gram-positive and gram-negative organisms, IToais are potent inhibitors of a wide range of ß-lactamases.

In combination with selected penicillins and cephalosporins, the compounds act synergistically against various bacteria producing β-lactamase because they protect penicillins 1 and cephalosporins against inactivation.

As mentioned above, the invention relates to new compounds intended in particular for enteral use I and having a strong antibacterial activity in vivo. The advantageous effect against bacteria producing β-lactamase is obtained because the compounds contain, in one and the same molecule, the remainder of a 6-amidinopenicillanic acid with high antibacterial activity and the rest of a potent inhibitor of β-lactar mase, however, two conditions are necessary to use this characteristic of the new compounds. They must be able to be absorbed from the gastrointestinal tract and be hydrolyzed during or after absorption with the release of amidinopenicillanic acid and the β-lactamase inhibitor. It turned out that these two conditions are met and that the compounds of the invention are therefore interesting precursors ("pro-drugs") both acids | amidinopenicillanics and ß-lactamase inhibitors.

| Thus, studies in animals and in human volunteers have shown that the new compounds are easily absorbed from the gastrointestinal tract. During or after absorption, they are hydrolyzed with liberation of equimolar amounts of the two components in question, 6-aminopenicylic acid! lanique and the ß-lactamase inhibitor, leading to simultaneous high levels of both components in the blood and tissue. Thus, 6-amidinopenicillanic acids are quite effectively protected against inactivation by ß-lactamases. The efficient absorption and hydrolysis in vivo of the compounds of the invention is illustrated by a study in volunteers. humans who have been orally administered one of the new compounds, 6 - [(hexahydro-1H-azepine-1-yl) -methylene-35 amino] hydrochloride, 1,1-dioxopenicillanoyloxymethyl penicillanate, known as | in the following VD-1825. / For comparison, the same group / 1 / H was also administered 5 groups of volunteers, equimolar amounts of pivaloyloxymethyl ester of 6 - [(hexahydro-1H-azepine-1-yl) -methylene- amino] penicillanic (mecillinam), pivmecillinam hydrochloride and potassium penicillanate 1,1-dioxide, respectively, which are orally active.

The results of these studies are collated in Tables I and II below.

It appears from Table I that the oral administration of VD-1825 leads to serum mecillinam contents similar to those obtained after an equimolar dose of pivmecillinam. It also appears from Table I that the urinary recovery of mecillinam after administration of VD-1825 is comparable to that obtained after administration of pivmecillinam.

As shown in Table II, only 4.3% of penicillanic acid 1,1-dioxide is excreted in the urine after oral administration of the corresponding potassium salt. On the contrary, the administration of an equimolar amount of VD-1825 gives a urinary recovery of 77% of the penicillanic acid 1,1-dioxide, thus thus illustrating the effective absorption of VD-1825.

The effective absorption and hydrolysis in vivo of the compounds of the invention are further illustrated by a study carried out in eight healthy, fasted human volunteers, who received an oral dose of 260 mg of VD-1825, HCl ( corresponding to 200 mg pivmecillinam, HCl) in a capsule. After administration, the levels of mecillinam and of penicillanic acid 1,1-dioxide in the serum are determined: the results appear in the attached single figure.

The dashed line curve indicates the serum levels of penicillanic acid 1,1-dioxide and the solid line curve indicates the serum levels of mecillinam.

It appears from the figure that the administration of VD-1825, HCl leads to simultaneous high levels of mecillinam and of β-lactaroase inhibitor and moreover that the latter is always present in substantially the same molar ratio and can therefore protect. effectively the mecillinam molecule against the influence of ß-lacta-35 mases.

The antibacterial spectrum of 6-amidinopenicillanic acid. in question is largely extended by the use of the compounds of λ / »6 sensitive to the treatment. These 1-lactamase producing strains are found with increasing frequency and are a serious problem in clinical therapy. The compounds of the invention prove to be of great interest for these applications. From the therapeutic point of view, the new compounds have clear advantages over the simple combinations of the amidinopecillanic acids and the β-lactamase inhibitors in which they are used. are hydrolyzed, or combinations of their active esters by oral use.

For example, several of the β-lactamase inhibitors, including penicillanic acid 1,1-dioxide, see Table II,! are poorly or irregularly absorbed from the gastrointestinal tract. Also, many amidinopenicillanic acids, including • mecillinam, are not fully absorbed when | 15 administered orally. In addition, individual variations j in the rate of absorption of the various amidinopenicillanic acids i and β-lactamase inhibitors can lead, in some cases, to a situation where the active components are not present simultaneously or in the optimal ratio , even if the two medicines are administered simultaneously.

Some readily hydrolyzable esters of araidinopenicillanic acid and ß-lactamase inhibitors are better absorbed from the gastrointestinal tract than the corresponding free acids. However, the hydrolysis of these esters in the body 125 leads to the formation of inactive by-products and, although these by-products are relatively non-toxic, it is undesirable to expose the body to unnecessary metabolites. Another disadvantage of using readily hydrolyzable ester combinations of derivatives, amidinopenicillanic acid and β-lactamase inhibitors is that the ester residues increase the molecular weight of the compounds and therefore the size of the compounds. j the dosing unit. By using the compounds of the invention, the size of the dosage units can be reduced considerably.

In addition, absorption of these esters does not normally take place simultaneously, even if the compounds are administered to the patient at the same time. For example, the pivaloyloxymethyl ester of I mecillinam is absorbed very quickly, while the sparingly soluble pivaloyloxymethyl ester of penicillanic acid 1,1-dioxide 'Ut // 7 (ß-lactamase inhibitor) is absorbed much more slowly.

All these drawbacks are avoided by using the compounds of the invention.

The Applicant has discovered that the in vitro synergy between the various β-lactamase inhibitors and various amidinopenicillanic acid derivatives is particularly pronounced when the ratio between the two components is between 3: 1 and 1: 3, like the various derivatives of amidinopenicillanic acid have slightly different biological periods and distribution characteristics} the ratio of components released from new compounds to organs and tissues may vary to some extent, but is normally between the limited preferred above.

The invention also relates to the preparation of the new compounds and their salts. According to a method of the invention, a compound of formula s is reacted

.. V

<7 N—

20 0 ir 'C-O-CH-X

H I

0 R2 in which R ^ and R2 are as defined above and X represents a removable residue such as a halogen atom, preferably iodine, with a compound of formula AM in which A is as defined above and M is a cation such as Na, K, an ammonium or tri- or tetraalkylammonium ion, for example a tetrabutylamraoniym ion.

The reaction is carried out in a suitable solvent, for example dimethylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphorotriamide, for a sufficient time and at a temperature suitable for carrying out the desired conversion, usually at a temperature of 0 to 60 ° C. ,

The compounds of formula X can also be prepared by a two-stage process. In a first step, a compound of formula A-M is made / reacted with a compound of formula VI A / y "8 Y-CH-Χ

1 VI

| J R2 11. in which R 2 and X are as defined above and Y represents I] 5 a removable residue, such as a bromine or iodine atony or a halosulfonyloxy group, for example chlorosulfonyloxy, alkylsulfonyloxy, || α-haloalkoxysulfonyloxy, or a residue (substituted or unsubstituted aryl) sulfo j | nyloxy such as benzenesulfonyloxy, tosylsulfonyloxy or bromobenzene-

sulfonyloxy, Y being a better removable residue than X, to give an intermediate of formula VII

IA-CH-X

R 711 * 2 in which R2, A and X are as defined above.

The reaction is carried out in the same manner as described for the preparation of the known compounds of formula V and it takes place in a suitable solvent, for example dimethylformamide, acetate.

Ethyl} dichloromethane, acetone or hexamethylphosphorus triamide, usually at a temperature of 0 to 60 ° C. j In a second step, the intermediary is reacted; 20. of formula VII with a derivative of araidinopenicillanic acid of formula R ^ CH-N ^

] VIII

• J—

25 0 Er C-O-M

If 0!; in which R ^ and M are as defined above, to form an ester of. formula I, If desired, X can be replaced in advance in formula VII by a better eliminable residue.

The above conversions are carried out in an organic solvent inert to the reaction, for example dimer! thylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphorotriamide under the conditions mentioned above, and usually at temperatures from 0 to 60 ° C. / il · ‘35 Another mode of implementation of the method comprises a '/ d 9

first step in which a compound of formula A-H is reacted with an ester of 6-aminopenicillanic acid of formula IX

VJVV

H

"

J — N—. IX

5 CT 4

H C-O-CH-X

He I

o r2 in which R2 and ^ are as defined above, or its amino-protected derivative, for example a trialkylesilyl derivative,

10 to give a compound of formula X

_L3

S

X

y — Tk;

0 r C-O-CH-A

It I 0 R2 15 in which R2 and A are as defined above. The reaction is carried out in a suitable organic solvent, for example dimethylformamide and preferably at temperatures from 0 to 30 ° C.

The intermediates of formula X can also be prepared. by reaction of a 6-aminopenicillanic acid or its salt or its amino-protected derivative with a compound of formula VII, i

In a second step, a compound of formula X or its trialkylsilyl derivative is reacted with a reactive derivative of an amide or thloamide of formula

R ^ -CH = Z XI

Wherein R ^ is as defined above and Z represents oxygen or sulfur to give an ester of formula I.

As examples of reactive derivatives of a compound of formula XI, non-limiting types of the following compounds may be mentioned: iminium chlorides, iminium-ethers, iminium-thioethers, acetals of amides. / U /% 10

Reactions with said reactive derivatives are well known to those skilled in the art familiar with the preparation of derivatives! amidinopenicillanic acid.

|! In another embodiment of the process, the compounds of formula 1 are prepared by reacting a compound of formula X or its trialkylsilyl derivative with a compound of formula I © r \

j H2N - CH-Z-R? XII

I in which X and Z are as defined above and R ^ is a lower alkyl or benzyl radical, the hydrogen atoms of the 6-amino group in formula X being replaced by a group R ^ -Z- CHe.

Without isolation of the reaction product, an amine of formula R ^ -H, in which R ^ is as defined above, is added to the mixture and a compound of formula I is obtained.

i! . The reaction is preferably carried out in an inert organic solvent such as ethyl ether, tetrahydrofuran, ethyl acetate or benzene at room temperature or at lower temperatures. The first part of the reaction takes place quickly and, after the addition of the amine R 1 -H, the reaction mixture is placed at room temperature or at a lower temperature until the reaction is complete. .

The intermediates of formula VII and X are compounds hitherto unknown.

I The starting materials of formulas V, VI, VIII, IX, XI

25 and XII are known, or they can be prepared by methods analogous to those used for the preparation of similar known compounds.

Most of the starting materials of formula A-M or the corresponding acids are known compounds. The new compounds are acids and salts in which A and a radical of formula II above, in which R 1 represents certain acylamino radicals. The latter compounds are penicillin sulfones which can be prepared by known methods.

The compounds of formula I can be purified and isolated / 35. in the usual way and can be obtained either in the free state / u / or in the form of salt. / U

• I

11 *

The compounds can in certain cases be obtained in the form of diastereomeric mixtures which, if desired, can be separated by known methods, for example by chromatography. The invention also relates to pharmaceutical compositions which are useful for the treatment of infectious diseases in human and veterinary medicine which can be used for enteral, parenteral or local administration.

To this end, the compositions of the invention contain as active component at least one of the compounds of formula formule and their salts as defined above, together with solid or liquid pharmaceutical carriers and / or diluents.

In these compositions, the proportion of the therapeutically active substance relative to the support can vary between 15 1 and 95% by weight. The compositions can be put in various pharmaceutical forms of presentation, such as tablets, pills, dragees, suppositories, capsules, slow release tablets, suspensions and the like containing the compounds of formula 1 or their non-toxic salts, mixed with carriers and / or diluents.

Solid or liquid, organic or inorganic, non-toxic, pharmaceutically acceptable carriers and / or diluents can be used to prepare the compositions containing the compounds of the invention, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols, tampons or other carriers, auxiliaries and / or diluents known for drugs are all suitable.

In addition, the compositions may contain other therapeutically active components which can be advantageously administered together with the compounds of the invention in the treatment of infectious diseases, such as other antibacterials, cough suppressants, analgesics, probenecid, etc. Antibacterials such as penicillins or cephalosporins, which have a synergistic effect with one or both of the active components formed by the in vivo hydrolysis of the compounds of the invention, are particularly suitable.

The compounds of formula I can be used either / --------- ^ t 12 soluble only in water, while several of the salts, for example hydrochlorides, are well soluble in water.

| As indicated above, the compounds of the invention ί can be put in pharmaceutical forms of presentation I 5 comprising the suspensions and the nonaqueous ointments. Uhe: | pharmaceutical preparation for oral treatment can! be in the form of a suspension of one of the compounds of the invention, | the preparation containing 10 to 100 mg of the active ingredient per ml of the vehicle.

The subject of the invention is also the choice of a dose of the compounds of the invention and of a dosage unit for the compositions of the invention, this dose and this dosage unit being able to be administered so as to obtain the desired activity without simultaneous side effects. In human therapy, the compounds of the invention are advantageously administered (to adults) in dosage units J of compositions containing not less than 50 mg and up to 2500 mg, preferably from 100 to 1000 mg, d active ingredient calculated ii as a compound of formula 1,

The term "dosage unit" means a unit dose, ie a single dose which is capable of being administered to a patient and which can be easily handled and packaged, while remaining in the form of a physically stable unit dose comprising either the active substance as such or in admixture with diluents, solvents, solvents and / or solid or liquid pharmaceutical auxiliaries.

In the form of a dosage unit, the compound can be administered once or several times a day at appropriate intervals, always depending, however, on the condition of the patient and the prescriptions of the practitioner.

Thus, a daily dose is preferably an amount of 0.25 to 15 g of a compound of formula X or an equivalent amount of its salt as defined above, which can be advantageously divided into several divided doses.

| In the continuous therapy of patients suffering from infectious diseases, tablets or capsules are the appropriate form of pharmaceutical preparation, if desired in the form of / i slow release formulations, / l / d:%

In veterinary practice, the above pharmaceutical compositions can also be used, preferably in the form of dosage units containing from 30 mg to 25 g of the compound of formula 1 or a corresponding amount of one of its salts.

For the treatment of mammary disorders, in particular mastitis in cattle, the antibacterial agent can be administered by the intramammary route in liquid or semi-liquid form, such as an ointment, or else in conjunction with a binding agent which is substantially insoluble in water and insoluble in oil in the form of granules.

The invention also relates to a method of treating patients suffering from infectious diseases, this method comprising administering to adult patients an effective amount of a compound of formula I, either as it is or in the form of a salt such as defined above, and preferably in the form of the above-mentioned dosage units. The compounds of formula I are typically administered in daily amounts of 3 - 200 rag per kg of patient's body weight, which corresponds to 0.25 - 15 g per day for adult humans, or an equivalent amount of one salt as defined above of a compound of formula I.

In the treatment of patients, the compounds of the invention can be administered either alone or with other therapeutically active compounds, for example probenecid, which helps to fight bacterial infection. This combined treatment can be carried out with formulations containing most or all of the therapeutically active compounds, or can be administered? in separate formulations, these being administered simultaneously or at appropriate intervals.

In the treatment of patients, the daily dose is administered either at once or in divided doses, for example two, three or four times a day,

The examples of preparations below illustrate more particularly the processes for preparing the new products and intermediates of the invention.

Preparation 1 To a stirred solution of 1.90 g (12 millimoles) of potassium permanganate in 35 ml of water and 1.36 ml (24 millimoles) ^? / acetic acid, a solution / u is added dropwise at 0-5 ° C.

• I

:. 14 I ice cream of 1.91 g (6 millimoles) of potassium 6a-bromopenicillanate in 25 ml of water. When the addition is complete (about 15 min), the mixture is stirred for a further 20 min at low temperature. The cooling bath is removed and 1.52 g (8 ml - 5 moles) of solid sodium pyrosulfite is added to the mixture to reduce excess oxidizing agent. The precipitated manganese oxides are filtered off and 20 g of sodium chloride are added to the filtrate (about 60 ml); solid and 50 ml of ethyl acetate. The mixture is adjusted to pH 1.5 by addition of 4N hydrochloric acid with stirring and the organic phase is separated. The aqueous phase is reextracted with 25 ml of ethyl acetate, the organic extracts are combined and washed with 1 d chloride. saturated aqueous sodium, dried and evaporated in vacuo. We crystallize j. the amorphous residue thus obtained in an ether-isopropyl ether mixture to obtain 6-bromopenicillanic acid 1,1-dioxide, mp 124-127 ° C.

j A crystallized potassium salt of the compound is obtained

, above by adding 3.6 ml of IM potassium 2-ethylhexanoate

in acetone to a stirred solution of 0.94 g (3 millimoles) of 6a-bromopenicillanic acid 1,1-dioxide in 12 ml of acetone.

The NMR spectrum of potassium 6α-bromopenicillanate 1,1-dioxide (CD ^ OD) shows signals at 1.48 (s, 3H; 2-CH ^) 1,5 1.59 (s, 3H; 2- CHg); 4.48 (s, 1H; 3-H); 5.10 (d, J "2Hz, 1H; 6-H); and 5.35 (d, J = 2Hz, 1H; 5-H) ppro. Tetramethyl-silane is used as an internal standard.

25 Preparation 2 lal; dioxYde_d2acide_6ot-çlilorogénicillanigue

By replacing potassium 6a-bromopenicillanate by potassium 6fl-chloropenicillanate in the procedure of Preparation 1, the 1,1-dioxide dioxide 6a-chloropenicil-30 lanique is obtained in the form of crystals in isopropyl ether , M 134-137 ° C,

The NMR spectrum (CDCl ^) presents signals at. £ = 1.50 (s, 3H; 2- (¾) j 1.64 (s, 3H; 2- (¾); 4.46 (s, 1Hj3 -g); 4.70 (d, J “1.5Hz, 1H; 6-H); and 5.18 (d, J = 1.5Hz, 1H; 5-H) ppm.

Tetramethylsilane is used as an internal standard (T.M.S.).

A crystallized potassium salt of the above compound is obtained by adding an equimolar amount of 2-ethylhexanaafce / 0.8 M potassium in acetone to a stirred solution of 1,1-diOHÿde A / acid 6ot-chloropéuicillanique -in acetone. / 1 / τ 15

Preparation 3 2-eniçillana te-de_clilgrgniéthxle Al-dioxide to a solution of 1.17 g (5 millimoles) of penicillanic acid 1,1-dioxide in 7.5 ml of dimethylformamide, 5,98 ml (7 millimoles) of triethylamine are added and 2.18 ml (30 millimoles) of ehloroiodomethane and the mixture is stirred at room temperature for 4 h. After dilution with 30 ml of ethyl acetate, the mixture is washed with 3 × 10 ml of water and then 5 ml of saturated aqueous sodium chloride, dried and evaporated in vacuo to obtain the desired compound 10 in the form of 'a yellowish oil which crystallizes in a mixed ether-petroleum ether, F 94-96eC.

The NMR spectrum (CDCl 4) shows signals at 6 1, 1.47 (s, 3H; 2-CH3) i 1.66 (s, 3H J 2-0¾); 3.53 (d, J = 3Hz, 2H; 6ot-H and 6β-Η); 4.46 (s, 1H; 3-H); 4.68 (t, J = 3Hz, 1H; 5-H); and 5.85 (ABq, J = 6Hz, 2H; OCHgCl) ppra. Tetramethylsilane is used as an internal standard.

Preparation 4

Following the procedure of Preparation 3, but replacing the chloro-methane with 1-chloro-1-iodoethane and increasing the reaction time up to 16 h, the penicillanate 1,1-dioxide is obtained by 1 -chloroethyl in the form of a yellow oil which can be purified by chromatography on a dry column of silica gel (ethyl acetate-petroleum ether, 7: 3).

25 Preparation 5

By replacing, in the procedure of Preparation 3, the penicillanic acid 1,1-dioxide by the 6a-bromopenicillanic acid 1,1-dioxide, the 6a-bromopenicil-1,1-dioxide is obtained chloromethyl lanate in the form of a yellowish oil.

The NMR spectrum (CDClj) exhibits signals at 1, 1.48 (s, 3H; 2-0¾); 1.64 (s, 3H; 2-CH3); 4.46 (s, 1H; 3-H); 4.71 (d, J “1.5 Hz, 1H; 6-H); 5.17 (d, J "1.5 Hz, 1H; 5-H); and 5.60 (ABq, J "6 Hz, 2H; OCHgCl) ppm. TMS is used as an internal standard. . /? h * '· 16 Preparation 6 6P — bromo ^ eniciXlanate_de_ctiXorornié tliyle' By replacing in the procedure of preparation3.

, j Island 1,1-dioxide of penicillanic acid and triethylamine by potassium 5-p-bromopenicillanate, the chloromethyl 6ß-bromop & icillanate is obtained in the form of a viscous oil.

i Preparation 7

Following the procedure of preparation 3, but j | Replacing the penicillanic acid 1,1-dioxide and the triethylamine by sodium clavulanate, chloromethyl clavulanate is obtained.

Preparation 8 lil-dioxYde_de_ ^ enicillanate <_dei_çhlorométh2jle I 15 To a suspension of 1.08 g of potassium penicllanate 1,1-dioxide in 12 ml of dimethyl formamide, 1.6 g of bis-chloromethyl sulfate are added and the mixture is stirred at temperature; room for 45 minutes. After dilution with 50 ml of ethyl acetate, the mixture is washed with water, then with sodium bicarbonate, dried and evaporated in vacuo to give an oil. which is purified by chromatography on silica gel, which gives the desired compound, identical to the compound described in Preparation 3.

; Preparation 9 i ΧΑX-dioxYda_de_6 "-chloro ^ eniçillanate_de_chlorométhYle 1 25 By replacing in the procedure of preparation 3 the 1,1-dioxide of penicillanic acid by the 1,1-dioxide of i 6a-chloropenicillanic acid, one obtains chloromethyl 6a-chloropenicillinate, 1,1-dioxide in the form of a viscous oil.

1 The NMR spectrum (CDCl ^) presents signals to; 30 S »1.48 (s, 3H; 2-0 ^); 1.64 <s, 3H; 2-0 ^) j 4.47 <8.1H; 3-H); -4.68 (d, J = 1.5 Hz, 1H; 6-H); 5.17 (d, J-1.5 Hz, 1H; 5-H); and 5.81 · (ABq, J = 6 Hz, 2H j OCHgCl) ppra, We use the TMS as an Internal standard,

Preparation 10 1A X — dioxl de ^ llaria t e_ ^ iodomët'h.yXe 35 To a solution of 5.6 g (20 millimoles) of 1,1-dioxide of chloromethyl penicllanate in 45 ml of acetone, 9 g / d are added; (y "17 of sodium iodide and the mixture is stirred at room temperature for 16 h. 115 g of precipitated sodium chloride are separated, the solvent is removed in vacuo and the residue thus obtained is treated with the acetate mixture ethyl ether (1: 1) 5 g of insoluble sodium iodide are filtered off and the filtrate is evaporated under reduced pressure.

The residual oil is purified by chromatography on a column of silica gel (ethyl acetate-n-hexane, 4: 6) to obtain the desired compound in the form of colorless crystals in ether, F 101-102 ° C.

Preparation 11 A. 6P-Benzyloxycarbonylaminopenicillinic acid 1,1-dioxide 15 A in a stirred solution of 63.5 g of 6β-benzyloxycarbonylaminopenicillanic acid and 18.1 g of potassium hydrogen carbonate in 1125 ml of water, a solution of 38 g of potassium permanganate in 915 ml of water is slowly added (approximately 45 min) at 0 ° G. During the oxidation, the reaction mixture is kept at pH 20. 6.5 by addition of dilute sulfuric acid. The insoluble material is removed by filtration and the filtrate is extracted with ethyl ether. The resulting aqueous phase is again filtered and, after the addition of 600 ml of ethyl acetate, it is acidified to pH 2.5 with stirring. The organic layer is separated and the aqueous phase is extracted with a further 2 x 300 ml of ethyl acetate. After drying, the ethyl acetate extracts are combined and evaporated in vacuo. The residue is recrystallized in a mixture of 250 ml of ethyl acetate and 500 ml of petroleum ether to obtain the pure compound F 153 - 154¾} 20 ["3J B + 146.9 ° (c = 1 , C2H50H at 96%.

30 B. 1,1-dioxide. oof-aminopenicillanic acid hydrate

A filtered solution of 15.3 g of 6P-benzyloxycarbonylarainopenicillanic acid 1,1-dioxide and 4 g of potassium hydrogen carbonate is hydrogenated in 160 ml of water on 5 g of 10% palletized BaSO 4 for 4 h under slightly elevated pressure. After filtration -35 tion and extraction with 100 ml of ethyl ether, the solution, ice-cold aqueous, is adjusted to pH 2.5. The precipitate is thus separated by filtration / * 18; j in the dimethylforraamide-water mixture gives the pure monohydrate; : i j «j | F 199 - 200 “C (decomposition) [a ^ e + 252.9 ° (c" l, dimethylforma-: 3 mide).

! Preparation 12 5 lAl “digxggenicillanate_de_chlorométhyl i | To a mixture of 2.7 g (10 millimoles) of potassium 1,1-dioxo-penicillanate, 6.0 g (60 millimoles) of potassium hydrogen carbonate and 0.34 g (1 millimole) of hydrogen sulphate! tetrabutylamroonium in 10 ml of water and 15 ml of dichloromethane,! 1.5 ml of chloromethyl chlorosulfate are added. After stirring for 1 hour at 30 ° C., the mixture is filtered and the organic layer is separated and dried over sodium eulfate. After dilution with 25 ml of propanol-2, the solution is concentrated to approximately 10 ml soub | vacuum and allowed to stand at 5 ° G for 1 h * Crystals are separated by filtration, washed with cold 2-propanol and dried in vacuo to give the desired compound as colorless crystals F 94 - 96 ° C.

Preparation 13 l4l “1-chloroethyl dioxopenicillanate 2o A a mixture of 40.7 g (0.15 mole) of potassium 1,1-dioxopenicil-lanate, 25.5 g (0.15 mole) of silver nitrate and 7.5 g of silver oxide in 750 ml of acetonitrile, 42 ml of 1-chloro-1-iodoethane are added, after stirring for 48 h at temperature; . ambient, the silver salts are separated by filtration and brought! 25 the filtrate A dried under vacuum. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with saturated aqueous sodium chloride, filtered, dried and evaporated in vacuo. Chromatography of the residue on silica gel (hexane-ethyl acetate, 3: 2), the desired compound is given in the form of a crystal mixture of the two diastereomers, mp 130-132 ° C, | Preparation 2 p.m. 1A1-dioxogénicillanate_ de_l- ± odoéth ^ le! To a solution of 30 g (about 0.1 mole) of 1-chloroethyl 1,1-dioxo-penicillanate in 100 ml of acetone, 35 g (0.2 mole) of sodium iodide are added and the mixture is stirred at room temperature for 3 days * λ thiosulfate / aqueous sodium is added and the acetone is removed in vacuo. The separated oil is dissolved in ethyl acetate and the solution is washed with water, dried and evaporated in vacuo. The residual oil is chromatographed on silica gel (hexane-ethyl acetate, 3: 1) to obtain a mixture (F 134-136 ° C) of the diastereomeric esters of 1-iodoethyl 5 and 1-chloroethyl, containing 40 % of the iodo compound, according to the determination of iodine by microanalysis,

Preparation 15 6P “bromogénicillaMte_de_chlorométhyl To a stirred solution of 0.96 g (3 millimoles) of 10 6P ** potassium bromopenicillanate and 1.80 g (18 millimoles) of potassium bicarbonate in 9 ml of water and 9 ml of ethyl acetate, 0.10 g (0.3 millimole) of tetrabutylammonium hydrogen sulfate is added, then 0.45 ml (4.5 millimoles) of chloromethyl chlorosulfonate and the mixture is stirred at room temperature for 15 1 h 30 min. The organic phase is separated and the aqueous phase is re-extracted with 9 ml of ethyl acetate. The combined organic extracts are washed with 2 x 5 ml of water, dried and concentrated to about 5 ml under reduced pressure. The concentrate was subjected to dry column chromatography on silica gel (petroleum ether-ethyl acetate 9: 1) to give pure chloromethyl 68-bromopenicillanate as an almost colorless oil.

The NMR spectrum (CDCl 4) gives signals to “1.54 (s, 3H; 2-¾); 1.70 (s, 3H; 2-¾); 4.54 (s, 1H; 3-H); 5.35 and 5.59 (2d, J = 4Hz, 2H; 5-H and 6-H) J and 5.77 (ABq, J = 5Hz, 2H î 25 OCH ^ Cl) ppm. Tetramethylsilane is used as an internal standard.

Preparation 16 To a solution of 0.82 g (2.5 mmol) of chloromethyl 6β-bromo-penicillanate in 5 ml of acetone, 0.75 g (5.0 mmol) of solid sodium iodide is added and after protection against light, the mixture is stirred at room temperature for 24 h. The precipitated sodium chloride is filtered off, washed with 2 x 1 ml of acetone and the filtrate is evaporated in vacuo to give an oily residue which is redissolved in 20 ml of ethyl acetate. The resulting solution was washed with 2 x 10 ml of water, dried over MgSO 4 and after concentration to approximately 5 ml under reduced pressure, chromatography on a column of silica gel using / d / ¥ 20 using a petroleum ether-ethyl acetate mixture 9: 1 as eluent, The fractions containing the desired pure compound, revealed by thin layer chromatography (TLC), are combined and evaporated under vacuum, to obtain iodomethyl ββ-bromopenicillanate in the form of a slightly yellowish oil. ·

The spectrum of RM presents signals to | 1.55 (s, 3H; 2- (¾); 1.69 (s, 3H; 2- (¾) d 4.50 (s, 1H; 3-H); | 5.34 and 5.57 ( 2d, J (4Hz, 2H; 5-H and 6-H); and 5.97 (ABq, J = 5Hz, 2h; OCH ^ I) PPm · Tetramethylsilane is used as internal standard.

10 Preparation 17 1A ¢ 2A ô ^ dLméthoxybenzamLdoJgënicillanate_de_çhlorométhyl 1.8 ml (18 millimoles) of chloromethyl chlorosulfate is added in 20 min at room temperature to a mixture of 6.2 g (15 millimoles) of acid 1,1-dioxo -6ß- (2,6-dimethoxybenzamido) penicillanic (methicillinsulfone), 8.7 g (87 millimoles) of potassium hydrogen carbonate, and 0.51 g (1.5 millimoles) of tetrabutylammonium hydrogen sulfate in 15 ml of water and 15 ml of dichloro-! methane.

After stirring for another 15 min, the phase is separated.

Organic, dried and evaporated in vacuo to give an oil which crystallizes from 96% ethanol to give colorless crystals F 142-143 ° C (decomposition). Two recrystallizations from the acetone-water mixture give the analytical sample F 154 - 155eC (decompon on sitlon); [α] £ υ - + 195 ° (c-1, CHC13).

25 Preparation 18 lAl; dioxo-6P; (246-dimethoxybenzamido) genicillanate_d ^ iodomethyl

3 g (20 millimoles) of sodium iodide are added to a solution of 2.31 g (5 millimoles) of chloromethyl penicillanate, l-dioxo-6P- (2,6-dimethoxy-benzamido) in 10 ml of acetone and the mixture was stirred overnight at room temperature. The addition of water precipitates the desired compound in the form of crystals which are collected by filtration and dried under vacuum; F 153 - 1566C (decomposition).

The product is dissolved in a mixture of acetone and 96% ethanol, the acetone is removed in vacuo and the desired compound / crystallizes. By repeating this procedure, the A / is raised

S

20 21 melting point at 169-170 ° C (decomposition); [a] ^ “+ 197 ° (c = l, chci3),

Preparation 19 5 By replacing in the procedure of the preparation) .5, potassium 6P-bromopenicillanate by potassium 1,1-dioxo-6a-chloro-penicillanate, the desired compound is obtained in the form of colorless crystals in the isopropyl ether-ether mixture; • F 111 - 113eC; [a] ^ 0 - + 210e (c = 0.5, CHClg).

10 Preparation 20 3: i.il ^ ï252lêÇiZ £ lii2 £ 2Ei2Î: £ iiiâ25Èê- ^ i2 ^ 25JÉ £ liïif

By replacing in the procedure of preparation 16.1e chloromethyl 6β-bromopdnicillanate by chloromethyl 1,1-dioxo-6a-chloropenicillanate, the desired compound 15 is obtained in the form of a colorless foam.

The spectrum of KM (CDCl ^) presents signals at 1.49 (s, 3H; 2- (¾); 1.62 (s, 3H; 2-¾); 4.41 (s, 1H; 3-H ); 4.66 and 5.16 (2d, J = 1.5 Hz, 2H; 5-H and 6-H); and 6.01 (ABq, J = 5 Hz, 2H; OGH ^ t) ppm. Tetraraethylilane is used as an international standard.

20 Preparation 21 1A l-d ± oxo-ôa-bromogénicillana te_de__chlorgméthYle

By replacing potassium 6β-bromopönicillanate in the procedure of Preparation 15 with potassium 1,1-dioxo-6a-bromo-penlcillanate, the desired compound is obtained as colorless crystals in the ether-ether mixture. isopropyl; 90 F 92 - 93 ° G; [a] Ju - + 185 ° (¢ - = 0.5, CHClg).

Preparation 22 l ^ l ^ dioxo-ôot — bromo ^ enicillana te_dj_iodornétliYle ", By replacing in the procedure of preparation 30 16, chloromethyl 6p-bromopenicillanate by chloromethyl l, l-dioxo-6ot-bromopenicillanate, the desired compound 'in the form of a colorless foam which does not crystallize.

The spectrum of RM (CDC1 ") presents signals to / J

δ »1.49 (s, 3H; 2-¾); 1.63 (s, 3H; 2-¾) J 4.41 (s, 1H; 3-H); 4.70 and 5.16 (2d, J-1.5 Hz, 2H; 5-H and 6-H); and 6.01 (ABq, J "5 Hz, / 22 \ Preparation 23] | By replacing, in the procedure for preparation il5, potassium δβ-bromopenicillanate by potassium 6P ~ iodopenicillanate 5, the desired compound is obtained as a slightly yellowish Î oil.

The NMR spectrum (CDCl 4) exhibits â! δ »1.52 (b, 3H; 2-CH3); 1.71 (s, 3H; 2-CR3); 4.55 (s, 1H; 3-H); J 5.4 ° and 5.63 <2di Jt = 3 "5 Hzj 2S" 5-H and 6 "I> î and 5.78 (ABq, J" 5.5Hz, 110 2Ή; 0CM2C1) ppm. We use tetramethylsilane as an internal standard *

Preparation 24 | êËZè2d2EÉ5 ^ 2iilê2§ £ § _ ^ - i2 ^ 2n? iÊbXl§ I By replacing in the procedure of preparation 16,1e 6ß-bromopdnicillanate of chloromethyl by 6P-iodopenicilla “15 chloromethyl nate, the desired compound is obtained in the form of a yellowish oil.

The NMR spectrum (CDCl ^) presents signals at δ - 1.53 (s, 3H; 2-CH3), 1.70 (s, 3H; 2-CH3), 4.53 (s, 1H; 3- H), 5.39 and 5.61 (2d, J “3.5 Hz, 2H; 5-H and 6-H), and 6.00 (ABq, J" 5.5 Hz, 20 2H; OCH ^ I) ppm, tetramethylsilane is used as internal standard

Preparation 25 §Êl2-i2Î2E-2i2iii222!: 2_d2_2! Îï: 2Î2 ™ ^ !: tiYl £ I By replacing in the procedure of preparation 15, potassium 6P-bromopenicillanate by potassium 6P-chloropenicil-25, obtains the desired compound in the form of a colorless oil.

The spectrum of .RMN (CDClg) presents signals at δ »1.53 (s, 3H; 2-CH3), 1.69 (e, 3H; 2-CH.j), 4.54 (s, 1H; 3-H), 5.24 and 5.62 (2d, J = 4 Hz, 2H; 5-H and 6-H), and 5.80 (ABq, J = 5 Hz, 2H} 30 OŒ ^ Cl) PPm · Tetramethylsilane is used as internal standard,

Preparation 26 §Ër2 ^ i2ï2E§2-2Î: ï-22â £ 2 - iÎ: 2d2ïï-2-Yi2

By replacing, in the procedure of Preparation 16, chloromethyl 6P-bromopenicillanate with 68-chloropenicil- / 35 chloromethyl lanate, the desired compound is obtained in the form / of a slightly yellowish oil, / u / τ "23 * · *

The NMR spectrum (CDC1 ^) presents signals at 1.52 (s, 3H; 2- (¾); 1.69 (s, 3H; 2-¾); 4.52 (β, 1H; 3-H ); 5.22 and 5.58 (2d, J-4 Hz, 2H; 5-H and 6-H); and 5.99 (ABq, J-5 Hz,.

2Ή; OCHgï) ppm. Tetramethylsilane is used as an internal standard.

5 Preparation 27 eP-bromo ^ enicdLllanate ^ of ^ cKl.orométh ^ Le * A. 6,6-chloromethyl dibromopenicillanate

By replacing, in the procedure of Preparation 15, the potassium 6P "bromopenicillanate with potassium 6,6-dibromopenicillananate, the desired compound is obtained in the form of a slightly yellowish oil which crystallizes in the ether mixture. 20 isopropyl ether; mp 105 - 107 ° C; ["] ^" + 206 ° (c * 0.5, CHCl ^),

The NMR spectrum (CDGl ^) shows signals at 6 1.54 (s, 3H; 2-¾); 1.66 (s, 3H; 2-¾); 4.60 (s, 1H; 3-H); 5.80 (ABq, J “5 Hz, 2H; O ^ Cl); and 5.83 (s, 1H; 5-H) ppm. Tetramethylsilane is used as an internal standard.

B. 6P “chloromethyl bromopenicillanate To a stirred solution of 1.63 g (4 millimoles) of chloromethyl 6,6-dibromopenicillanate in 40 ml of dry benzene, added under nitrogen atmosphere at 0 ° C, 1, 16 g (4 millimoles) of trl-n-butyltin hydride. After stirring at room temperature for 18 h, the mixture is evaporated in vacuo. The residual oil is purified by chromatography on a dry column of silica gel (petroleum ether-ethyl acetate, 85:15) to obtain pure chloromethyl 6P-bromopenicillanate in the form of a slightly yellowish oil.

The NMR spectrum of the product is identical to that of the compound described in preparation 15.

Preparation 28 30 1A1-digxg2 ^ n ± c ± î-lanafce_ de_bromométh3f le To a solution of 1.0 g of sodium bromide in 10 ml of N, N-diroethyl £ ormamide, 0.28 g (1 millimole) is added of chloromethyl 1,1-dioxo * penicillanate and the mixture is stirred at room temperature for 20 h. After dilution with 50 ml of ethyl acetate, the mixture is washed with 4 × 10 ml of water, dried and evaporated in vacuo. The residue is purified by chromatography on nit vf.

** 24 column of silica gel to give the desired compound in form i. a yellowish oil; ; The NMR spectrum (CDCl ^) presents signals to! 6 »1.49 (s, 3H; 2- (¾); 1.64 (s, 3H; 2-0¾); 3.52 (m, 2H; 6-H); H 5 4.47 (s, 1H j 3-H) J 4.75 (m, 1H; 5-H); and 5.98 (ABq, J = 4.5 Hz, 2H; OC ^ Br) ppm. TMS is used as internal standard.

The following examples illustrate the invention without however limiting its scope.

Π i j; Example 1 '10 ÇÎii2H ^ Y ^ E5ï®_ ^ ®_§z [(hexahydro; M-azéBine-l-Yl) -méthxl | nM ^ no2; g | niçll · · lS2âHf - ê-iâi'ÏI-i252Ei & è £ îï3iS52ïl2525} i £ \ iïl2 To a solution of 1.87 g (5 millimoles) of chloromethyl 6 - [(hexahydro- ji 1H-azepine-1-yl) -methyleneamino] penicillanate is added 1 , 36 g (5 millimoles) of potassium penicillanate 1,1-dioxide and the mixture was stirred at room temperature for 48 h. 75 ml of ethyl acetate are added and the mixture is washed with 4 x 25 ml of water to remove the dimethylformamide. The remaining organic phase is dried and discolored by stirring with charcoal. After separation of charcoal 20. by filtration and concentration of the filtrate to approximately 30 ml, ‘25 ml of water is added and the apparent ρΉ of the mixture is adjusted to 2.6 by addition! 4N hydrochloric acid with stirring. The aqueous phase is separated and freeze dried to give the desired compound as an i! amorphous powder.

! The NMR spectrum (D ^ O) shows signals at <5 "= 1.48 and 1.55 (2s, 6H; C (CH3) 2); 1.60 and 1.72 (2s, 6H J 0 (0¾) ^ i 1.68 (b, 8H; C ^ ÇH ^ C ^); 3.65 (m, 6H; ÇH ^ NC ^, 6a-H and 6β-Η);! 4.68 (s, 1H; 3-H);. 4.75 (s, 1H; 3-H); 5.08 (dd, JL * 4 Hz, J2 * 2 Hz, j 1H j 5-H); 5.56 (d, J "4 Hz, 1H; 6-H); 5.68 (d, J-4 Hz, 1H; 5-H); | 30 6.02 ( s, 2H; ΟΟΗ ,, Ο); and 8.03 (s, 1H; N-CH "N) ppm. | Tetramethylsilane is used as an external standard.

Isopropanol is added to a solution of 0.5 g of the above product in 1.5 ml of raethanol until a haze is formed; and crystallization is started by scraping the wall. After rest! In the refrigerator for 24 h, the crystals are separated by filtration, / they are washed with isopropanol and dried under vacuum to give it. 25 “sought compound in the form of a colorless crystalline product having a poorly defined melting point (slow decomposition above 120 * 0.

"

The IR spectrum (KBr) shows bands at "1690 and 1790 (wide) cm *" 1.

5 Example 2

1.41 g (5 millimoles) of chloromethyl penlcillanate 1,1-dioxide are added to a solution of 1.63 g (5 millimoles) of 6 - [(hexahydro-1H-azepine-1-yl) acid. -methyleneaminojpénicillanique and 0.7 ml (5 millimoles) of triethylamine in 25 ml of dimethylformamlde and the mixture is stirred 4 at room temperature for 16 h. After dilution with 75 ml of ethyl acetate, the mixture is washed with 4 x 20 ml of water and the remaining organic phase is dried and discolored with charcoal. The carbon is separated by filtration and 35 ml of water are added to the filtrate. The apparent pH of the mixture is adjusted to 2.8 by adding 2N hydrochloric acid with stirring. The aqueous phase is separated and lyophilized to give an amorphous compound identical to that obtained in Example 1.

20 Examples 3 to 11

By replacing, in the procedure of Example 2, the 6 - [(hexahydro-1H-azepine-1-yl) -methyleneamino] penicillanic acid with the amidinopenicillanic acids listed in Table XIX below, the compounds are obtained correspondents of formula X.

25 Example 12

SiiI§2â £ ë-éS - ?: ZÎliïZ ^ i2ï2Eé2Î: £ Î: î: Ï22223: 22Zl-E!} Xi2

By replacing, in the procedure of Example 2, the chloromethyl penicillanate 1,1-dioxide with 1-chloroethyl penicillanate 1,1-dioxide, the hydrochloride of 6 - [(hexahydro “III) is obtained. -azepine-1-yl) -methyleneamino] l- (1,1-dioxopenicillanoyloxy) ethyl penicillanate in the form of a colorless foam.

Example 13

^ - [(Hexahydro ^ 1H ^ azegine-1-yli-methyleneamino ^ geni-35 gnianate ^ hydrochloride ^ 1 ^ dioxogeniçillanoyloxymethyl / To a cooled mixture of 5.85 g (18 millimoles) of acid // 6 - [(hexahydro-1H-azepine-1-yl) -methyleneamino] penicillanic and jjf /; * 26; ί: 6.12 g (18 millimoles) of tetrabutylammoniura hydrogen sulfate in: dd 35 ml of dichlororaethane and 35 ml d with water, 18 ml of 2N aqueous sodium hydroxide are added with stirring. The organic layer is separated, the aqueous phase is re-extracted with 15 ml of dichlororaethane and the combined organic extracts are dried over MgSO 4 and evaporated under empty.

The colorless oil thus obtained is dissolved in 100 ml of ethyl acetate and the resulting solution is concentrated under reduced pressure to approximately half its volume. A solution of 5.6 g (15 millimoles) of iodomethyl penicillanate 1,1-dioxide is added to the concentrate in one portion and the mixture is stirred at room temperature for 10 min. The precipitated tetrabutylammoniura iodide is filtered off, 75 ml of water are added to the filtrate and the apparent pH of the stirred mixture is adjusted to 3.0 with 1 N hydrochloric acid at 5 ° C. The aqueous phase is separated and covered with 50 ml of ethyl acetate and the pH is adjusted to 7.2 by addition of 0.5 M aqueous sodium hydrogen carbonate with stirring. After separation of the organic layer, 50 ml of water are added and the stirred mixture is adjusted to pH 3.0 with 1 K hydrochloric acid. The aqueous phase is separated and dried by freezing to give the desired compound. as a colorless amorphous powder.

A solution of 5 g of the above product is diluted in 15 ml of ethanol with approximately 20 ml of isopropanol until a cloudiness appears and is sown. After stirring at room temperature for about 1 hour, a heavy crystalline precipitate formed. The mixture is gradually diluted with 40 ml of isopropanol and kept at 5 ° C. for 3 h. The precipitate is separated by filtration, washed with isopropanol and then with ether and dried under vacuum to give the hydrochloride of 6 - [(hexahydro-1H-azeplne-1-yl) -methyleneamino] penicillanate, 1-dioxopenicillanoyloxymethyl 30 in the form of colorless crystals having a poorly defined melting point (slow decomposition above 120 ° C), identical to the product described in Example 1.

Example 14

Chlorh ^ dra te_de_6 ~ £ ChexahYdro ^ lH-azégxne-l-yl) -méthylèneaming ^ EÉSiZ

35 clavulanoyloxymethyl cillanate I By replacing, in the process of Example 1, potassium penicillanate / 1,1-dioxide with f l clavulanate // /

I T

. 27 sodium and reducing the reaction time to 16 h, the desired compound is obtained in the form of a yellow foam.

Example 15 Hydrochloride e_de_6- [(h exahydro-1H-a zegine-1; Yl) -raethYlèneamino] genid.l-5 lanate_de_ltl-dioxo-6û-chlorogén.icillanoyloxyméthyl

Following the procedure of Example 2, but replacing chloromethyl penicillanate 1,1-dioxide with chloromethyl 6,1-chloropenicillanate, the desired compound is obtained in the form of a powder. yellowish.

Example 16 6 - Hydrochloride - [(hexahydro-1H-azégine-1-yl) -methyleneaminojgenicil-lana te _de_§ß "bromopenici1lanoyloxymethyl

By replacing, in the procedure of Example 2, chloromethyl penicillanate 1,1-dioxide with chloromethyl 6-bromo-penicillanate, the desired compound is obtained in the form of an amorphous powder.

Example 17 Hydrochloride_62 [£ hexahydro-1 (2H) -azocin; 1-yl2 “methyleneamino] geniil lanate _de_l! L 1 ^ dioxogenici 1 lanoyloxymethyl 20 Following the procedure described in Example 13 and replacing the acid 6- [(hexahydro-1H-azepine-1-yl) -methylene-aminojpenicillanic acid 6 - [(hexahydro-1- (2H) -azocin-1-yl) -methylenearainoj-penicillanic, the desired compound is obtained in the form a colorless lyophilized powder.

The NMR spectrum (CD ^ OD, with TMS as internal standard 3) shows peaks at i · 1.46 (s, 3H; 2- (¾); 1.57 (s, 6H; 2- ¾) i 1.74 (s, 3H; 2- (¾); 1.5-2.0 (m, 10H; (¾) ^; 3.2-3.8 (m, 6H; (CH ^ N, 6a -H and 6ß-H); 4.48 (s, 1H; 3-H); 4.63 (s, 1H; 3- H); 4.93 (m, 1H, 5-H); 5.53 (d, J = 4 Hz, 1H} 6-H); 5.63 30 (d, Jn4 Hz, 1H, 5-H); 5.97 (s, 2H; OCHgO); and 8.18 (s, 1H; N-CH = N) ppm.

Example 18 Hydrochloride_6 - [(hexahydro-1H-azégine-1-yI) “methyleneamino] geni- £ iil§üêÎë_d2_lr (li.l:" dioxogénicillanoyloxy) ethyl 35 A solution of 4.53 g (8 millimoles) of 6- [(hexa- / / / d * • * 1.28 ammonium in 40 ml of ethyl acetate, a solution of i 8.13 g (purity 38 corresponding to 3.09 g B 8 millimoles) of 1 is added 1-iodoethyl 1,1-dioxopenicillanate in 25 ml of ethyl acetate.

I After stirring for 5 min at room temperature, the precipitated tetrabutylammonium iodide is filtered off and washed with ethyl acetate. The desired compound is transferred from the filtrate | in 40 ml of an aqueous phase with hydrochloric acid N (pH 3.0, Ί at 5 ° C) and of the aqueous phase in 40 ml of an organic phase I (ethyl acetate) with hydrogen carbonate of sodium qqueux 10 (pH 7.0 at 5 ° C), The organic phase is washed with water and the desired compound is again transferred to an aqueous phase as described above. The drying by freezing of the aqueous phase gives the | J: desired compound in the form of a colorless solid, \\ j. The NMR spectrum (D ^ O) shows peaks & 1 15 δ * 1.50 (s); 1.56 (b), 1.61 (s); 1.66 (d, J-7) 5.17 (s); 1.5-2.0 (m) d 3.20-3.85 (m); 4.61 (s); 4.75 (s) to 5.10 (m); 5.53 (d, J "4); 5.68 (d ^ -4) i! 7.05 (q, J = 7); and 8.03 (s).

i j | Example 19 20 9 ^ 1§î} âte_de_lilzdioxoz6 “(2i6-diinethoxybenzainido) penicillanoyl; OXY-methyl

0.7 g (2 millimoles) of 6 - [(hexahydro-1H-I azepine-1-yl) -methyleneamino] penicillanate is added to an ice-cold solution of 1.11 g (2 millimoles) of l, l -dioxo-6- (2,6-dimethoxyben- dj 25 zamido) iodomethyl penicillanate in 10 ml of dimethylformamide, 1 After stirring for 30 min at room temperature, the mixture is diluted> the mixture with 40 ml of acetate and washed with 4 x 10 ml | . of water.

| The organic phase is stirred with water, adding 30 hydrochloric acid to pH 3. The aqueous phase is dried by freezing to give the desired compound in the form of a colorless powder,

The NMR spectrum (CD ^ OD, with TMS as internal standard presents signals at δ * 1.47 (β, 3H; 2- (¾); 1.58 (s, 6H; j 35 2-0¾); 1.76 (s, 3H; 2-0¾); 1.25-2.25 (m, 8H; ((¾) ^; 3.5-4.0 (m, '4H; ((¾) ^) ; 3.83 (β, 6H; 0¾); 4.67 (s, 1H; 3-H); 4.70 i (β, 1H; 3-H) j 5.29 (d, J-4 Hz, 1H; 5-H); 5.5-5.8 (m, 2H; 5-H and / 1 / "f" • * 29 6-H); 6.03 (m, 2H} 0CH20)} 6, 26 (d, Ja4 Hz, 1H; 6-H); 6.71 (d, 2H; 3-H and 5-H aromatic); 7.41 (t, 1H; 4-H aromatic j and 8.21 ( s, 1H, N-CHbN) ppm.

Example 20 5 6 - [^ hexahYdro2lH; azégine; l-Yl); mét'hYlèneamino] péniçillanate_âe £ i «Yï 3: - - 22 i22Xïl thy 1 e

0.1 g (0.5 millimole) of lithium elavulanate is added to a solution of 0.23 g (0.5 millimole) of 6 - [(hexahydro-1H-azepine-1-yl) -methyleneamino] penicillanate iodomethyl in 3 ml of hexamethylphOBphorotriamide. After stirring for 90 min at room temperature, diluted with 20 ml of ethyl acetate and washed with 4 × 10 ml of water. The organic phase is stirred with 20 ml of water, adding hydrochloric acid to pH 3. The aqueous phase is separated and stirred with 10 ml of ethyl acetate by adding sodium bicarbonate. aqueous sodium up to pH 7. The organic phase is dried and evaporated to give an oil which is purified by chromatography on 8 g of "Sephadex Uâ-20). The desired compound is isolated in the form of a colorless oil.

. The NMR spectrum (CDC1 ^, with TMS as internal standard shows signals to & el, 49 (s, 3H; 2-CH ^); 1.65 (s, 3H; 2-CH3); 1.4 -2.0 (m, 8H; (¾) ^; 3, U (d, J = 17 Hz, 1H; 6ß-H); 3.48 (dd, J = 17Hz, J = 3 Hz, 1H; 6 <xH); 3.3-3.6 (m, 4H; (CH2) 2N); 4.22 (d, J = 7 Hz, 2H; (Μ ,, ΟΗ); 4.4l (s, 1H; 3-H); 4.91 (t, Ja7H, 1H, G-CH); 5.08 (s, 1H; 3-H); 5.18 (d, J = 4 Hz, 1H; 6-H) ; 25 5.51 (d, J = 4 Hz, 1H; 5-H); 5.68 (d, J = 3 Hz, 1H; 5-H); 5.87 (m, 2H; 0-CH20) ; and 7.60 (s, 1H; N-CH = N) ppm.

Example 21 Hydrochloride_6; [(hexahydro; 1H-azégine-1-yl) 2methyleneaming] geniçil; laMteede_6P-bromogénicillanoyloxyméthyl 30 Add 535 g (1.68 millimole) of potassium 6ß-bromop4nicillanate to a solution of 6.52 mg (1.40 millimole) of 6 - [(hexahydro-III-azepine-1-yl ) -methyleneamino] iodo-methyl penicillanate in 15 ml of dimethylformamide. After stirring for 30 min at room temperature, the mixture is diluted with 60 ml of ethyl acetate and washed with 4 x 15 ml of water. The organic phase is separated and concentrated in vacuo to about 20 ml. * / • 15 ml of water are added to the concentrate and the apparent pH of the mixture is adjusted to 30 with agitation. addition of 0.5 H hydrochloric acid. The aqueous phase is separated and dried by freezing to give the desired compound as a colorless foam.

1 *

The NMR spectrum (D ^ O) presents signals at dd 5 6 = 1.48 (s, 3H; 2- (¾); 1.51 (s, 3H; 2-¾); 1.62 (β, 3H;! 2-¾); 1.68 (s, 3H j 2-¾); 1.4-2.0 (m, 8H; (¾) ^; 347-375 J (m, 4H; <Œ2) 2N); 4.71 (s, 1H; 3-H); 4.76 (s, 1H; 3-H); 5.46, 5.59, 5.62, and 5.66 (4d, J ~ 4 Hz, 8H; 5-H and 6-H); 5.93 (s, 2H; 0CH20); and 7.97 (s, 1H J N-CH "N) ppm.

"10 Example 22 i ChlorhYdrate_de_6 - [(hexahYdro-1H-asepin“ l- ^ l); méth ^ lèneamino} génicll “| Following the procedure described in example 21, but replacing 6ß-bromopdnicillanate by 6a -iodopenicilla-15 potassium nate, the desired compound is obtained in the form of a colorless powder.

The IR spectrum (KBr) shows strong bands & 1780 i -1 d and 1680 cm, I Example 23 '20 Çhlorhydrate_de_6 - [(hexahYdro-1H-azégine-l “Yl); méthYlèneamino] géni-çillanate ^ de ^ l ^ l-dioxopénicillano ^ loxjméthjrle A, 6P-tetrabutylammoniiim A aminopénlcillanate A stirred ice-cold mixture of 4.32 g (20 millimoles) I 68-aminopenicillanic acid, 6.8 g (20 millimole) tetrabutylammonium hydrogen sulphate , 50 ml of dichloromethane and 20 ml of water, a solution of 1.60 g (40 millimoles) is added slowly. sodium hydroxide in 3.5 ml of water. The organic layer is separated and the aqueous layer is extracted with 2 x 25 ml of dichloromethane. The combined organic layers are dried and evaporated under vacuum to obtain the desired compound in the form of a viscous oil,

The IR spectrum (CHCl ^) shows strong bands at 1760 and 1610 cm

B. Sbï2HÎî2-H2 £ S - 2-êll2ÏÏÎ52Eê2iSiiltSâiS-ë2-lAÏZÔi2ï2I

! ^ EiSi2iî: l§S2Y]: 2? YÎ! ÉÈlîX2: § / To a solution of 5.1 g (11 millimoles) of 6ß-araino- //. tetrabutylammonium penicillanate in 25 ml of ethyl acetate, / r / • 31 a solution of 3.73 g (10 millimoles) of 1,1-iodomethyl penicillanate dioxide in 25 ml of acetate is added ethyl. After stirring for 15 min at room temperature, the mixture is separated, precipitated by filtration and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on "Sephadex LH 20” using a chloroform-hexane mixture 65:35 as eluent. The purified product is dissolved in 25 ml of ethyl acetate, 25 ml of water are added and the mixture is adjusted to pH 2.0 by addition of 2N hydrochloric acid

The aqueous phase is separated and dried by freezing to obtain the desired compound as a colorless powder.

The NMR spectrum (D20) presents signals at h π 1.52 (s, 3H; 2-¾); 1.60 (s, 3H j 2 ^ ¾); 1.65 (s, 3H; 2- (H3); 15 1.76 (s, 3H j 2-¾); 3.52-3.8 (s, 2H} 6-H); 4.78 (s , 1H; 3-H); 4.90 (s, 1H j 3-H); 5.05-5.25 (m, 1H; 5-H); 5.20 (d, J “4 Hz, 1H i 6 -H) j 5.78 (d, J = 4 Hz, 1H; 5-H); and 6.08 (broad s, 2H; OGy)) ppm.

TMS is used as an external standard.

G. §5z2ïïï22EÉ2ï £ iïîSB2î: 2..s! 2..1iïl§3: 2ï2EÉ2i: 2iîï222Yi2? YZ

20 methyl

The hydrochloride obtained according to Example 23 B is dissolved in water and cooled in an ice bath. Ethyl acetate is added and saturated aqueous sodium hydrogencarbonate is added with stirring until the pH of the aqueous phase is about 7.

The organic phase is separated, dried and evaporated in vacuo, leaving the desired compound as a yellow oil.

D. ÇÎÎÏ2ïÎ} Y ^ Hâ £ ê- ^ ê_§z [ihexahydro-1H-azégine-l-yl); inéthy- llneaminojpéniçillanate ^ e ^^ - dioxogénicillanoyloxyméthyl In an ice-cold solution of 1.43 g of 1-thioforniyl-30 hexamethyleneimine in 20 ml of dry dichloromethane, 1.90 g of triethyloxonium tetrafluoroborate is added. The solution is stirred for half an hour at room temperature and cooled again in an ice bath. An ice-cold solution of 4.15 g of 1,1-dioxopenicillanoyloxymethyl 6P-aminopenicillanate and 1.80 ml of N, N-diisopropylethylamine in 20 ml of dichloromethane is added and the reaction mixture is slowly concentrated to about 0. ° C, After about 3 h, all the solvent is evaporated. The a / residue is extracted with 3 × 100 ml of ethyl ether and the ether extract $ / d / y il is dried. * j 32 i and it is treated with charcoal. 100 ml of water are added, the apparent pH is adjusted to 2.5 by addition of 2N hydrochloric acid and the aqueous phase is dried by freezing to give the desired compound in the form of an amorphous powder. This is identical I 5 to the compound described in Example 1. ·

Example 24 j Chlorh ^ drate_de_6- £ ÇhexaKYdro — XH-azégitte — 1 —— mét'h ^ lferjeamitioQgéii ^ “To a solution of 4.15 g of 6P-aminopenicillanate 10 of 1,1-dioxopenicillanoyloxymethyl and 3.2 ml of triethylamine in 25 ml of dry chloroform free from alcohol, drop by drop is added! drop 2.0 g of 1-chloromethylenehexamethyleneirainium chloride | j in 10 ml of dry alcohol-free chloroform at a temperature of approximately - 20 ° C. After standing for 30 min at -20 ° C, the temperature is raised to 0 ° C in 15 min. The solution is evaporated in vacuo

The residue is stirred with 150 ml of ethyl ether and the undissolved triethylamine hydrochloride is filtered off. 50 ml of water are added and the apparent pH of the mixture is adjusted to 2.5 by addition of 2N hydrochloric acid. The aqueous phase is separated and dried by freezing to give the desired compound in the form of | of an amorphous powder. This is identical to the compound described in | Example 1, t. It is understood that the invention is not limited to the preferred embodiments described above by way of illustration and that the person skilled in the art can make various modifications and various modifications without however departing from the framework and spirit of the invention, / en 33 "

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TABLE III

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11 cis-S-azabicyciotAjSjOJnonyle-S

(. * \

Claims (30)

1 * 4 36 1. New derivatives of penicillanic acid, characterized in that it corresponds to the general formula i: ’J — J ... - 1! 0 H C — 0 — CR — A! i. . j; - o * 2 i ·! '. in which R ^ represents an azacycloalkyl or azabicyclo- residue! 5-10 membered alkyl, linked by the nitrogen atom and optionally substituted by one or two identical or different lower alkyl groups; R ^ represents a hydrogen atom or a lower alkyl, aryl or arylalkyl radical; A represents a radical of a β-lactamase inhibitor containing a β-lactam nucleus as well as a carboxy group, A being linked by the carboxy group j and their acid addition salts. i * 2. Compounds according to claim 1, characterized in that they consist of pure diastereomers of formula I, as well as their salts and their mixtures, in the case where at least one of the residue i R. and of the ester residue contains a chiral center. I 1 3. Compounds according to claim 1, characterized in that A is chosen from a) the radicals of formula II q q! \? : R, j, R3 "4 <· 1 *"! % "! 11 '25 1-N- i cr%, c-o-! In which R ^ represents a hydrogen or halogen atom; R ^ is a hydrogen atom or an amino or acylamino group, and at least one / J '30 of the residues R ^ and R ^ is hydrogen; / ¥ b) the radicals of formula III / g '' T * 1 *: * * 37 ΙΊ Rc Λ H HS! 5 si_ III · H C-0- II 0 5 in which R ,. represents a halogen atom; and c) radicals of formula IV: r-fV 'IV i ° 0. c-o- II 0 in which Rg represents a hydroxy group or one of the radicals of the known derivatives of clavulanic acid; and their acid addition salts. 4. Compounds of formula I according to claim 3, characterized in that A represents a radical of formula II, and R ^ both represent hydrogen, and their acid addition salts. 5. Compounds of formula I according to claim 4, characterized in that A represents a radical of formula III, R ^ represents a halogen atom, and their acid addition salts. 6. Compounds according to claim 5, characterized in that R ,. represents bromine or iodine. 7. Compounds of formula I according to claim 3, characterized in that A represents a radical of formula IV, and Rg represents a hydroxy group, and their acid addition salts. 8. Compounds according to claim 1, characterized in that R ^ represents a plperidino residue, hexahydro-1H-azepine-1-yl, hexahydro-1 (2H) -azocin-1-yl, octahydro-1H-azonine-1 -yle, 2-methyl-hexahydro-1H-azepine-1-yl, 3-methylhexahydro-1H-azepine-1-yl, / 4-methylhexahydro-1H-azepine-1-yl, 2,6-dimethylpiperidino, cis- 3- * / azabicyclo [3,3,0] octyl-3 or cis-8-azabicyclo [4,3,0] nonyle-8, / jy 1-: 9. Compound according to claim 8, characterized in that R ^ represents a hexahydro-1H-azepine-1-yl group, and represents! a hydrogen atom. 10. Compounds according to claim 1, characterized in | 5 that they are chosen from 6 - [(hexahydro-1H-azeplne-1-yl) -methylene- I amino] 1,1-dloxopenicillanoyloxymethyl penicliianate, 6 - [(hexahydro-1 (2H) " 1,1-dioxo-penlcillanoyloxymethyl, azocine-1-yl) -methyleneamlno] penicillanate, 1, 1-l-dioxo-6- (2, 6-diraethoxybenzamido) -pénicilla-10 noyloxymethyl, 6 [(hexahydro-1H-azepine-1-yl) -methyleneamino] clavulanoyloxymethyl peni-cillanate, 6 - [(hexahydro-1H-azepine-1-yl) -methylen l- (1,1-dioxopenicillanoyloxy) ethyl \ lno3penicillanate, 6 - [(hexahydro-1H-azepine-1-yl) -methyleneamino] PP-bromopenlcillanoyloxymethyl peniclllanate, and 6 - [(hexahydro-l- 1-yl) -15 6-iodopenicillanoyloxymethyl methyleneaminolpenicillanate, and their acid addition salts. 11. Process for the production of the compounds of formula 1 according to claim 1, characterized. in that a compound is reacted "I formula 20 _ .. HH _ ycH-Kv, 's V CY HV' 'CO-CH-X Il I 0" 2 in which and R2 are as defined above above and X represents a removable residue such as a halogen atom4 with a compound of formula AH in which A is as defined above and H is a cation. 12. Process for the production of compounds of formula I according to claim 1, characterized in that a compound <[e formula R1 -CH = N ^ j;, VIII * / J-N-φ "is reacted. U 0. C-O-M Lf Il V 35. 0 l ·. »39 +,» dam £ where R ^ and M are as defined above, with a compound. of formula A-CH-X 'VII 2. 5 dan® which A, and X are as defined above. 13. A process for the production of the compounds of formula I according to claim 1, characterized in that a “compound of formula io vVf * \ X J1 — N — 7k is reacted. H CO-CH-A II I o r2 15 dan® which R ^ and A are as defined above, or are derived from trialkylsiiyle with a reactive derivative of an amide or thi-Oamide of formula R1-CH = Z XI dan® which R ^ is as defined above, and Z represents 20 l * c ": ygene or sulfur. 14. Process for the production of the compounds of formula I according to claim 1, characterized in that a compound of formula X above is reacted with a compound of formula Θ Θ HjH "CH-Z-IL X XII 25 where® X and Z are as defined above and is a lower alkyl or benzyl radiol, the hydrogen atoms of the 6-asnino group in formula X being replaced by a group R7-Z-CH = and sas ® isolation of the reaction product, an amine of the molecule R ^ -H, in which R ^ is as defined above, is added to the mixture. 15. The method of claim 11 or 12, characterized in that "X represents iodine. . / 16. The method of claim 13, characterized in thatÆ / 7 40 • "" the reactive derivative of formula XX is an iminium chloride, an irai-nium ether, an iminium thioether or an acetal amide. 17. Process according to any one of claims 11 to 16 for the production of 1,1-dioxopenicillanoyloxymethyl 6-((hexahydro-1H-azepine-1-yl) -methylene-1-yl) -penicillanate and its j | acid addition salts, characterized in that the corresponding starting compounds V, VII, VIII, X, XX and XII are used, j, 18. The method of any of claims 11 to 14, further characterized in that the compound of formula 1 is recovered as it is or in the form of an acid addition salt. 19. New drug, useful in particular as an antibiotic "against organisms producing ß-lactaraase, characterized in that it consists of compounds of formula I according to claim 1 and their non-toxic acid addition salts acceptable in pharma-15 co. 20. Medicaments according to claim 19, characterized in that A is a radical of a known derivative of clavulanic acid endowed with activity inhibiting ß-lactamase. 21. Therapeutic compositions, characterized in that they contain as active ingredients, at least one medicament according to claim 19, in combination with pharmaceutically acceptable carriers and auxiliary agents. 22. Compositions according to claim 21, characterized in that they contain 1 to 95% of the active ingredient. 23. Compositions according to claim 22, characterized in that they also contain a known penicillin, the ratio between the active compounds being from 1:20 & 20: 1, preferably from 1: 5 to 5: 1. 24. Compositions according to claim 19, characterized j ί 30 in that the active ingredient is 6 - [(hexahydro-1H-azepine ~ l-yl) - j methyleneamino] 1,1-dioxopenicillanoyloxymethyl penicillanate, optionally in the form a non-toxic acid addition salt acceptable in pharmacies, and penicillin is 6 - [(Da-amino-c £ - (p-hydroxyphenyl) ce tamido] penicillanic acid, 25. Pharmaceutical forms of administration of the compositions according to claim 21, in particular by enteral, parenteral or local route for the treatment of infectious diseases in medicine. / human or veterinary /// "" Γ * "41 26, pharmaceutical form according to claim 25, charac terized in that it comprises as active ingredient 0.025 to 2.5 g of a medicament according to claim 19, in combination with a non-toxic intake acceptable in pharmacies. 27. Pharmaceutical forms according to claim 25 for oral treatment, characterized in that they contain 0.05 to 1.5 g of the active ingredient, 28. Pharmaceutical forms according to claim 25, characterized in that the active ingredient is chosen from 6 - [(hexahy-dro-1H-azepine-1-yl) -methylhneamino] 1,1-dioxo- penicillanate; penicillanoyloxymethyl, 6 - [(hexahydro-l- (2H) -azocin-l-yl) -methyl-leneamino] 1,1-dioxopeniclllanoyloxymethyl penicillanate, 6 [(hexahydro-lH-azepine-.l ~ yl) - 1,1-dioxo-6- (2,6-dimethoxybenzamido) -penicillanoyloxymethyl, and methyl 6-[(hexahydro-1H-azepine-1-yl) -methyleneamino] clavulanoyloxymethyl penicillanate, and their salts addition of non-toxic acids acceptable in pharmacies. 29. Pharmaceutical forms according to claims 27 and 28, characterized in that they are presented in tablets, pills 20 or capsules, 30. Pharmaceutical forms according to claim 25, characterized in that the daily dose is from 3 to 200 mg / kg of body weight of the active ingredient of formula 1 or an equivalent amount of one of its salts. Drawings: —A .----------- plates „iL.iL .... pages including —A— cover page • 3.J * description pages. & ......... popes of claim ............ descriptive abstract: Luxembourg,! e. 12 / FEV, 1980 Charles München * *